Energy metabolism is essential for all living cells, particularly during periods of rapid growth or stress.
Cancer cells, activated immune cells, and yeasts predominantly rely on aerobic glucose fermentation to
generate ATP. This phenomenon is termed the ”Warburg effect” in cancer cells and the ”Crabtree effect”
in yeast cells [1]. Recently, several mathematical models have been proposed to theoretically explain the
Warburg effect.

Beyond glucose, glutamine is an important substrate for eukaryotic cells, playing significant role not
only in biosynthesis but also in energy metabolism. In this study, we develop a minimal constraint-based
stoichiometric model to explain the Warburg effect, incorporating the experimentally observed utilization
of glutamine (the WarburQ effect) [2]. Our model considers both glucose and glutamine respiration, as
well as the fermentation of these metabolites. By accounting for enzyme masses when calculating the
ATP production rates, our resource allocation model reflects the costs associated with different pathways.

Our results indicate that glucose fermentation is a superior energy-generating pathway in human
cancer cells. However, the characteristics of yeast homologues diminish this advantage or lead to the
situation when glucose respiration is more effective. The latter observation is consistent with the behavior of the fungal pathogen Candida albicans, which is known to be a Crabtree-negative yeast. Our results also demonstrate that glutamine serves as a valuable energy source under glucose-limited conditions, in addition to its role as a carbon and nitrogen source in eukaryotic cells. Moreover, the results effectively explain the observed simultaneous uptake of glucose and glutamine.

References

[1] Noureddine Hammad et al. “The Crabtree and Warburg effects: Do metabolite-induced regulations participate in their induction?” In: Biochimica et Biophysica Acta (BBA)-Bioenergetics 1857.8
(2016), pp. 1139–1146.

[2] Jing Fan et al. “Glutamine-driven oxidative phosphorylation is a major ATP source in transformed
mammalian cells in both normoxia and hypoxia”. In: Molecular Systems Biology 9.1 (2013), pp. 1–11.